Subsidized by the Program of the European Research Council - Advanced Grant

Neurodegenerative diseases are a considerable burden on the elderly population of Europe. Parkinson's disease affects 1.2 million people in Europe and, with the increase in life expectancy, this number will rise to increase pressure on healthcare systems.

Treatment of Parkinson's is symptomatic and there is an urgent need to find more efficient therapies. Degeneration of mesencephalic dopaminergic (DA) neurons trigger the initial phases of Parkinson's, which gives rise to the notion that cell replacement may be a long-term repair option for this neurological disease.

Indeed, previous studies in Parkinson's patients have shown that cell therapy has the potential to provide significant, long-lasting relief of symptoms. However, a weakness of these studies was the lack of an ideal source of transplantable human DA neurons. Recently, the production of induced pluripotent stem cells (iPSC) by reprogramming somatic cells has opened the door to the possibility of generating specific individual neurons with a high therapeutic potential.

We recently developed a methodology that promotes the transdifferentiation of mouse and human fibroblasts in functionally induced dopaminergic nerve cells (iDAN). The iDAN cells show complex neural properties, including pacemaker activity, synaptic integration, dopamine release based on activity and D2 functional autoreceptors. Therefore, iDAN cells provide a previously unknown source with ideal characteristics for cell therapy in Parkinson's, as they can be produced in patients in large quantities. Here, we propose improving the technology in humans and deciphering the molecular events.

We will then develop for in vivo reprogramming methods that locally promote neuron transdifferentiation in the mouse brain. Finally, we will attempt to perform autologous transplants of iDAN cells in monkeys with Parkinson's. Overall, this project will improve cell-reprogramming technologies and even aims to generate a better source of cells for transplant in patients with Parkinson's.